ABSTRACT: BACKGROUND:Open-label quetiapine coadministration with SSRI therapy, in a diagnostically mixed sample of comorbid anxiety patients, offered additional anxiolytic benefit. Therefore, we designed the following controlled trial to confirm these findings in a comorbid, SSRI-resistant, panic disorder (PD) patient sample. METHODS:This was a single-site, double-blind, placebo-controlled (PLAC), randomized, parallel group (2 groups), 8-week, quetiapine extended release (XR) coadministration trial. SSRI resistance was determined either historically or prospectively. Patients were randomized if they remained moderately ill (CGI-S score ? 4). Change in the PDSS scale total score was the primary efficacy outcome measure. Responders were identified as those with a ?50 % decrease from their baseline PDSS score. In the early weeks of therapy, XR was flexibly and gradually titrated from 50 to 400 mg/day. RESULTS:43 patients were screened in total, and 26 of these were randomized and evaluable. 21 patients (78 % of the randomized group) completed the trial (10 XR; 11 PLAC). The endpoint quetiapine XR mean daily dose ± SD was 150 ± 106 mg. While, in the sample as a whole, there was improvement in PDSS scores across the 8-week trial (ANOVA main effect of time, F = 10.9, df 8,192, p < 0.0001), the treatment × time interaction effect was not statistically significant (F = 0.8, df 8,192, p = 0.61). There was no between-group difference in responder frequency at endpoint. CONCLUSIONS:This proof-of-concept RCT did not support the efficacy of this treatment strategy for SSRI-resistant PD. Quetiapine XR was generally well-tolerated. Important limitations were the small sample size, and the relatively low average dose of quetiapine XR used. ClinicalTrials.gov ID#: NCT00619892.